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Prediction of epigenetic mutations effects in non-conserved regions

Epigenetic Mutations in Non-Conserved regions (EpiMutNC) is an open-accessed web tool for prediction of functional effects of amino acid substitutions in non-conserved regions of genes involved in epigenetic regulation.

Introduction

Single nucleotide polymorphisms (SNPs) are recognized as the main cause of human genetic variability. A non-synonymous SNP (nsSNP) is a single base change in the coding region of a gene that results in a single amino acid substitution (SAP) in the corresponding protein product. nsSNPs can significantly alter protein function and thus, the cellular and organismal phenotype of an organism. The main challenge ahead is to differentiate between neutral versus pathogenic SNPs that assign susceptibility to Mendelian disorders, common complex diseases, as well as cancers. Tools for predicting these functional effects are mostly phylogeny-based, and as such have high accuracies in predicting disease-associated mutations in conserved positions in protein sequences. However, we have shown recently that accuracies are significantly lower in classifying variations outside conserved functional domains (CFDs).

We developed a new tool, EpiMutNC, for prediction of effects of single amino acid substitutions outside conserved functional domains based on the model that relies on informational spectrum method for sequence analyses. It was implemented in Java programming language and it is available as user friendly web service. As input data, it uses position of the variation and substituted amino acid, and provides binary classification with graphical representation of the variation as output.

Our tool was trained and tested on the datasets of the gene variations in epigenetic regulators ASXL1, DNMT3A, EZH2, and TET2, a set of key biomarkers in myeloid malignancies. It significantly outperformed state of the art tools, PolyPhen-2 and SIFT.

References
Gemovic B, Perovic V, Glisic S, Veljkovic N. (2013) Feature-based classification of amino acid substitutions outside conserved functional protein domains. Scientific World Journal. 2013. 17;2013:948617.